Molecular mechanisms in hippocampal impairment induced by endocrine disrupters

内分泌干​​扰物引起海马损伤的分子机制

• 批准号: 11839011
• 负责人: KATO Nobumasa
• 金额: $ 2.3万
• 依托单位: Tokyo University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11839011/
• 关键词: endocrine disrupter; organotin compound; hippocampus; glucocorticoid receptors; glia; cytokine; cell death; behavioral and learning impairment; 有機スズ; 学習障害; トリメチルスズ; 神経細胞死

The present study was conducted in order to study the molecular mechanisms of the impairment in hippocampal functions following the administration of trimethyltin (TMT). TMT is a byproduct of certain plastics, and closely related to well known endocrine disruptors, tributyltin and triphenyltin. TMT was found to induce a profound loss of CA3 pyramidal cells as well as a moderate loss of CA1 cells, starting 4-5 days after dosing. This neuronal death was preceded by an early and transient elevation of plasma corticosterone, which was partially blocked by the pretreatment of interleukin-1 receptor antagonist. Behaviorally, TMT intoxication was characterized by an early and transient development of seizures, followed by a persistent aggression and learning impairments. It is thus suggested that TMT induced an early activation of hypothalamo-pituitary-adrenal axis, presumably preceded by the involvement of immuno-active cytokines, which may trigger the neuronal death via glucocorticoid (GC) receptors in the hippocampus.Further study was designed with use of a combination of adrenalectomy and administration of type I and II specific GC-receptor agonists. The suppression of an early elevation of plasma corticosterone by means of metyrapone adinistration resulted in the rescue of CA1 cell death, but not of CA3 cells, and subsequently, at least a partial improvement of learning impairments., Dexamethasone, a type II GC receptor agonist, but not aldosterone, a type I receptor agonist, blocks both the neuronal and behavioral impairment in TMT rats. The involvement of cytokines such as IL-1α and -1β were also examined. Supplemental treatment with corticosterone or dexamethasone cancelled adrenalectomy-induced enhancement of IL-1α and-1β expression, suggesting that TMT-induced OL-1α and-1β production was regulated via type II GC receptors.

本研究旨在探讨三甲基锡(TMT)致大鼠海马区功能损害的分子机制。TMT是某些塑料的副产品，与众所周知的内分泌干扰物三丁基锡和三苯基锡密切相关。从给药后4-5天开始，TMT可引起CA3锥体细胞的严重丢失和CA1细胞的中度丢失。在神经元死亡之前，早期和短暂的血浆皮质酮升高，这可以被白细胞介素1受体拮抗剂的预处理部分阻断。在行为学上，TMT中毒的特征是早期和短暂的癫痫发作，随后是持续的攻击和学习障碍。因此，TMT诱导了下丘脑-垂体-肾上腺轴的早期激活，可能是免疫活性细胞因子的参与，这可能是通过糖皮质激素(GC)受体在海马区引发神经元死亡。进一步的研究采用肾上腺切除和给予I型和II型特异性GC受体激动剂相结合的方法。用甲孕酮抑制早期血浆皮质酮升高可挽救CA1细胞死亡，但不能挽救CA3细胞，从而至少部分改善学习障碍。地塞米松是II型GC受体激动剂，但不能阻断I型受体激动剂醛固酮，可阻断TMT大鼠的神经元和行为障碍。同时检测IL-1α和-1β等细胞因子的参与情况。补充皮质酮或地塞米松可阻断肾上腺切除诱导的IL-1α和-1β表达的增强，提示TMT诱导的OL-1α和-1β的产生是通过II型GC受体调节的。

项目成果

高橋良斉,森信繁,加藤進昌: "大脳辺縁系 海馬とストレス"ブレーン出版. (2000)

Yoshiaki Takahashi、Nobushige Mori、Nobumasa Kato：“边缘系统海马体和压力”Brain Publishing。

森信 繁 他: "臨床生化学・神経内分泌検査からみたPTSDの病態"臨床精神医学. 29(1). 41-47 (2000)

Shigeru Morinobu 等人：“从临床生物化学和神经内分泌测试中观察到的 PTSD 病理学”《临床精神病学》29(1) (2000)。

金井裕彦,西村敏,池田正行,相身良成,石田展弥,石倉菜子,綱島浩一,加藤進昌: "海馬てんかん焦点形成に対するグリア活性化と一酸化窒素合成酵素の役割について"てんかん治療研究振興財団研究年報. 12. 45-53 (2000)

Hirohiko Kanai、Satoshi Nishimura、Masayuki Ikeda、Yoshinari Aimi、Nobuya Ishida、Nako Ishikura、Koichi Tsunashima、Nobumasa Kato：“神经胶质活化和一氧化氮合酶在海马癫痫病灶形成中的作用”癫痫治疗研究促进基金会研究年度报告。 12. 45-53 (2000)

N.Ishida, S.Yasuda, N.Kato: "Experimental models of generalized seizures and epilepsy."Advances in Neurological Sciences. 44. 23-35 (2000)

N.Ishida、S.Yasuda、N.Kato：“全身性癫痫发作和癫痫的实验模型。”神经科学进展。

Y.Takahashi, S.Morinobu, N.Kato: "Hippocampus and stress. In ; The Limbic System.Eds.T.Itakura and T.Maeda."Brain Pub.Co.Ltd.Tokyo. 103-118 (2000)

Y.Takahashi、S.Morinobu、N.Kato：“海马体和压力。在；边缘系统。Eds.T.Itakura 和 T.Maeda。”Brain Pub.Co.Ltd. 东京。